About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

September 18, 2007

Ugly, But Useful

Posted by Derek

I also mentioned recently that I’d come across a good example of an academic compound with interesting activity but no chance of being a drug. Try this one out, from Organic Letters. Yes, there aren’t many other compounds that do what this one does (inhibit the production of TNF-alpha). And no, it’s not going to be a drug – well, at least the odds are very, very long against it.

Why so negative? Several reasons. For one thing, this molecule is extremely greasy. This is not a killer in and of itself, but it’s inviting trouble, for the reasons noted here. The second problem is that this thing looks like it’s going to have some trouble dissolving. That’s trouble both from both the thermodynamic (eventual amount in solution) and kinetic (speed of dissolution) senses. That greasiness will be the problem with the former, since a lot of this molecule’s surface area gives water molecules no incentives to join in on anything. And all those aryl rings (along with the symmetric structure) are asking for trouble with the latter. Those features make the structure look like it’ll form a very good, very happy crystal, with its aromatic rings stacked onto each other like ornamental bricks. “Brick” is the very word that comes to mind, actually.

But solubility is only the beginning. The real problem is that catechol functionality in the center of the molecule, which is just waiting to turn into a quinone. In medicinal chemistry, no one wants quinones; no one likes them. They’re just too reactive. It would not surprise me for a minute to learn that this group, though, is the reason for the compound’s activity. It’s probably reacting with some functional group on the surface of the target protein and gumming up the works that way. It’ll do that to others, too, if it gets the chance. There are all sorts of weird little quinones in the literature that hit proteins that nothing else will touch, but none of them are going anywhere.

No, it’s safe to say that any experienced drug-company chemist would draw a red X through this one on sight. Plenty of reasonable-looking compounds turn up with unanticipated problems, so we don’t need to go looking for trouble. That’s not to say that it can’t be a research tool (although I’d be careful interpreting the data from complex systems – there’s no telling how many other things that quinone is going to react with).

But all this brings up another thing that we were talking about around here – how much do drug companies owe academia for working out fundamental biochemistry and molecular biology? What if someone uses this very compound, for example, as a research tool and discovers something about its target that could be used to develop an actual drug? What do we call that?

Well, we call that “science”, as far as I can see. Everything is built on top of something else. In a case like this, the discoverers of this current compound, even if they’ve patented it, do not have a claim on what discoveries might come from it later on. An even stronger case was decided in that direction – the University of Rochester’s discovery of the COX-2 enzyme, the patent for which led to their attempt to claim revenue from Celebrex. The judge ruled, absolutely correctly in my opinion, that the discovery of a drug target is not the discovery of a drug, and that the effort and inventiveness needed for that second step is more than enough for it to stand on its own.

There’s a “research exemption” for patents, giving legal room to use the disclosed inventions and compounds to make further inventions. I think that’s an extremely important concept. It lets academic labs study patented industrial compounds for their own purposes, and it even lets companies do that to each other. How would we compare our internal compounds to the competing ones if we couldn’t use them? (There’s more than one research exemption, though, and the traditional common-law one took a big hit a few years ago in Madey v. Duke, which worries me).

I strongly oppose broad patent claims for uses and pathways, because I think that these cut into legitimate research. Patents should cover things that are novel and useful. They should completely disclose the substance of their invention. And in return for the period of exclusive rights, anyone else who wants to should be able to get to work on what will replace them. A patent is not a license to kick back; it’s a reminder to keep moving.

This is a fascinating look at how drugs get developed, and of how much work goes into finding compounds that are both useful AND practicably usable as medicines to fight the diseases that plague us. Just as a heads-up to your readers, I’ve been involved in launching a new public service site where people can share their stories of survival and recovery from dreaded diseases, or of coping with chronic conditions, as a way to inspire others who may be similarly challenged. Again, it is entirely a public service, a place where people can find hope. If anybody is interested, they can go to http://www.sharingmiracles.com/.

I agree that Vialinin has a lot of problems, but none are insurmountable IF the SAR is forgiving. But all other things being equal (affinity, selectivity, etc.), one would certainly prefer a more drug like molecule as a starting point for medicinal chemistry optimization.

In addition to the long litany of sins that Derek lists, one could add high MW (563) and the thing looks like a frequent hitter (apparent activity for reasons other than specific high affinity binding to the target protein; e.g., formation of aggregates that coat proteins).

Why isn't this considered an opportunity? A chance for the experts in industry to solve the very problems Derek mentioned. There is also a symmetry problem (solubility) and that was solved in the HIV-protease area and it can be done here.

I am not talking specifically about vialinin A. My academic colleagues do not subscribe to the "NIH funded research is responsible for everything" that has been discussed lately. In fact, I have never heard anyone state that other than on this blog or in a poorly written book.

What I have heard and I believe is that current pharmaceutical company environment, both corporate as well as scientific level, is risk-averse. They are expecting much more data prior to even considering new projects from academic or biotech collaborators. I certainly understand that as a business model. However, the cyclical elimination of scientific intellect to save a few bucks I can't understand.

Calling the pharma industry risk averse is like claiming Britney is publicity shy. There aren't too many other major industries that carry more risk than biotech/pharma. The whole business is about high risk/high reward.

Look at all the cash being invested in siRNA. How much has been invested in other things such as gene therapy, combichem, etc with no guarantee of anything coming out at the end. Name another industry that takes on that kind of risk on a consistent basis.

Biotech and small pharma should not be lumpled with big pharma. Any company willing to accept risk would also accept short term losses (weak gains) in favor of long term success. Thats not big pharma.

And your choice of combichem simply supports my point. It was a business decision not a scientific one. Replace educated people with robots. It should save money and increased output per FTE obviously means increased drugs.

great article, long time reader and first time poster. I'm studying for my prelim and need to find the mechanism of diazomethane generation from diazald but am coming up empty on all ends. Can anyone point me in the right direction. Thanks.

RET- I am not sure I agree about combichem being a way to replace FTEs with robots. I am sure that thought crossed people's minds, but I think the greater motivation was statistical. More compounds = more hits = more INDs. Saving money is rarely a prime motivation for pharma/big biotech.

I believe your assessment in correct Jose regarding combichem. It was never about replacing people, it was about getting more hits.

RET - Even if it were about reducing cost, which it wasn't, would that not be risk-taking, in the sense that you are trying a relatively unproven technology? And what would you call a clinical program if not short term loss for long term gain? Only about 10% that enter the clinic ever make it to market and even in Phase III there is a significant failure rate, and a Phase III trial can run into the 100's of millions. Is that not assuming and accepting risk? The industry by it's very nature is all about risk.

The other thing you wrote was "It was a business decision not a scientific one." So business decisions can't contain risk?

I agree with Jose... Combichem was used (poorly) to build complexity into HTS collections, not to replace lead opt chemists. I think a modern analogy to combichem would be the use of fragment library screening to generate leads.

I wasn't around when all of this happened, but my guess is that some academics hyped it in consulting meetings and companies took the bait. If you read those articles before the experiment was done, they do make a compelling argument. It's too bad most combinatorial libraries lack true diversity. I wonder if there were any naysayers who predicted it's failure...

So the academics are to blame for combichem? I remember having dinner with Jon Ellman and a bunch of Lilly folks in 1997 and they questioned him about his vision of the future of the pharmaceutical industry. He reminded them that he was simply an assistant prof trying to do some interesting research.

I guess academics overhype biologically active compounds and pharma ignores us but when it came to combichem it was taken hook, line, sinker. To get the facts straight, Parke-Davis (doesnt exist anymore despite the discovery of blockbuster drugs) was a major player in combichem hype. As I stated already, greater output per FTE means more drugs; business not science. If it was not about cost then the same business people would have said "more chemists means more compounds which means more drugs." The calculations were done and combichem was cheaper than increasing scientific staff.

"So business decisions can't contain risk"

Of course, there is risk in every decision but success doesnt come from taking the least risky route all the time.

Derek –
I’m surprised there were not more comments on this post. This is a topic that I think about periodically – particularly after meetings or discussions around “new” targets. Invariably at least a portion, and many times most, of work around target identification and validation comes from academia. This research is undoubtedly supported by our tax dollars. Should salary, prestige from publishing and the warm feeling for doing quality science be the extent of their reward for contributing to the identification of a drug? For what it’s worth, that’s exactly what I get.
But should the NIH or other funding organization get a return on their “investment”? For the record, the funding is typically in the form of grants, meaning that the money is used at the discretion of the PI in order to pursue the topic in the grant proposal with no obligation to repay. This is by far not a novel point, but I believe that the government and the people get their return through the introduction of a new product, the good that it does, the jobs that are created to make it, the tax dollars that are generated from doing that business… and so on and so on…
Is this fair in the end? Who knows. But the Government holds a trump card in terms of tax rates, industry regulation and perhaps soon, a great influence over the price that can be charged for any drug. And the People also hold a card (maybe not trump). Public perception of the industry and the extent people will go to avoid paying what are perceived to be exorbitant prices can put negatively affect the overall business.

RET: most academics we have as consultants are nowhere nearly as humble as Ellman. And not all of the technologies we waste money on come from academics... we get swindled by other companies/biotechs too. Pharma doesn't ignore academics that discover compounds either... it's just that there's so much noise because every crappy lead structure gets hyped as the next miracle cure.

---If it was not about cost then the same business people would have said "more chemists means more compounds which means more drugs."---

Simple math tells you that's impractical... business sense is not necessary. Even if chemists were free, without some sort of combinatorial technology, it would take an army to generate the number of compounds combichem enables. Besides, throwing people at a "no leads" problem gets you nowhere fast.

"Of course, there is risk in every decision but success doesnt come from taking the least risky route all the time."

Once again, RET, your bias comes through. You assume that a "business" decision is de facto the least risky route. Not at all. There are tons of decisions made in all sorts of industries that are not the safe decisions. I'll give you an example.

Hyundai's decision to implement a 10-year, 100,000 mile warranty program. Considering their previous track record and what was industry standard, everyone thought they were absolutely bonkers. It was an incredibly risky move, but they did it. They challenged themselves to increase quality and they challenged the consumer to think differently about the brand. It's been very successful, but it was also very risky.

The combichem discussion is relatively tangential to my original point, which was that pharma is anything but risk adverse.

There were some beautiful careers built on the combichem argument, some of which have now migrated their allegiance to fragment- based advantages... Most people who felt negative about the combichem 'groupthink' kept their heads down as that opinion was not acceptable.
I remember a notable exception, an experienced medicinal chemist at Roche who was brave enough to openly say something along the lines of 'the next development candidate from Roche will not come from an impure lyophilised smear in the bottom of a vial'.

Should salary, prestige from publishing and the warm feeling for doing quality science be the extent of their reward for contributing to the identification of a drug? For what itâ€™s worth, thatâ€™s exactly what I get.

You make it sound trivial, but if you played a key role in the characterization of ACE or HMGCR, the rewards that flow to you (including consulting fees -- you forgot consulting fees) are pretty lavish in the context of that line of work: prominence, tenure, job prospects for your postdocs, sure-thing approval of your grant applications, consulting fees.

But should the NIH or other funding organization get a return on their â€œinvestmentâ€�?

They're getting paid up front by Congress to make contributions like that.

"Now what is this "no leads" problem you speak of?
Any chance the inclusion of a few riskier projects might provide a few more leads?"

It's the risky projects which don't have leads... thus the problem. Without structural information, no validated hits from a high throughput screen, and no tractable lead structures from literature/competitors, what do you do? I think the thought was that combichem would help companies cover more structural space causing a higher hit rate in HTS and that hasn't turned out well.

I work at a major pharmaceutical company, and I can safely say that we have several high-risk programs. We hedge our bet with others that are lower in risk... anything where the mechanism of action isn't fully understood or where there is no clinical proof of concept in humans is inherently risky.

I think we're in agreement that compounds made individually by chemists are higher in quality, both in terms of purity and drug-likeness, but hiring chemists to make compounds willy-nilly doesn't seem that bright either. The more recent approaches have been to buy chemical libraries from companies who sell them... it turns out that many of those libraries aren't much better than combinatorial ones, and they sell the same libraries to your competitors, so if you get a hit, you had better work quickly.

You're using "business decision" pejoratively, which doesn't make sense to me. If an academic were confronted with a similar problem, would you expect him/her to develop a tool for making a ton of compounds or would you expect them to hire a post-doc army?

I apologize for the fact that initial point was continually modified through the comment section. I simply said that I don't count the investment in combichem as an example of risk-taking by the pharmaceutical industry. It made perfect sense financially but many of the chemists asked to work in this area understood the problems quite quickly (from diversity to data management to purity). That what I meant a business decision.

Also I think you would be more successful with a postdoc army with each bringing their own creativity to the group than to come up with a tool to make a ton of molecules that all look the same.

There is nothing wrong with outsourcing. I see no reason to believe that the quality of research (discovery or process) cant be just as good in a geographic area with lower overall costs. The pharmaceutical industry is a business although I do not think that high Wall street expectations are much help in finding "tomorrows miracles."

To be specific my biggest pet peeve is that big pharma gave up on natural products as potential lead compounds despite their prevalence in the current pharmaceutical arsenal. They certainly have structural diversity and they are the most likely sources of finding new biological targets.

Second, I have lots of friends in med chem who feel their creativity is squelched by an atmosphere of what Derek said happend in combinatorial chemistry "make what is easy." I believe creativity at the expense of productivity needs to rewarded.

"To be specific my biggest pet peeve is that big pharma gave up on natural products as potential lead compounds despite their prevalence in the current pharmaceutical arsenal. They certainly have structural diversity and they are the most likely sources of finding new biological targets."

Well, we still has a natural products group. I think most gave up on them because they wanted to create drugs outside of antibiotics and anti-cancer cytotoxics.

I was trained with natural products, and I'm proud of the work I did in the field, but I contend that they are not the most likely source of finding new biological targets. They're a tool, and sometimes they work out, but there are way more powerful tools these days. Most of the targets I've seen in my department have come from molecular biology or some form of genomics.

Another problem with natural products is that mother nature didn't necessarily design her chemical weapons for once a day oral dosing. If you have to do any optimization of the structure, you run into danger of having to synthesize a complex molecule on scale, or doing a complex semi-synthesis from a fermentation. It just doesn't make sense to seek out complexity if it's not needed.

Regarding being told to make what is easy -- That's a shame. Attitudes regarding creativity and innovation vary from company to company (and sometimes even site to site). Time is a major factor, so creativity stifling may come from a desire to move quickly. It's a shame for your friends... I haven't had the same experience.

Not a novel concept by Chris, but a great mnemonic and real contribution encapculating a lot of medicinal chemistry knowledge. Of course this compound (vialinin A) won't be a drug, as you say Derek, but some clues to trying to fix it are well enunciated in the literature.

But as with all medchem problems, they may not work with the requisite potency/efficacy/bioavailability/pharmacological consistency/manufacturability/formulatability/tolerability intact, along with the scores of other attributes necessary to turn a potent biochemical modulator into a commercial drug.

There are also other quite interesting TNF production inhbitors out there if one looks closely.

Good point about about cancer and antibiotics but you can add antifungals (which is still a unmet need) and the statins. This all modes of action (biological targets) that likely coincide with the activity in their producing organism. It certainly should be possible to find new targets with NP simply based on their structural diversity.

I am particularly interested in what your company does to promote or at least allow creativity particular when it comes to yearly evaluations.

Are you sure it was the University of Rochester? I was sure it was BYU, and they were suing for revinue based on an information sharing agreement that they felt they had lived up to, but that Pfizer didn't.

Kay, I guess I don't agree. Not having worked at Pfizer, I don't know how Chris' analysis was implemented there, but the "rule of 5" for instance explicitly acknowledged that only four of five parameters need be followed and certainly any scientist who ignores positive data in order to respect a mnenomic should turn in their bona fides.

My view, only that, is that what Chris did was to distill some basic parameters from what used to be mystically referred to as "medchem instincts" and put them in a very simple form which, as with aforemention instincts, may be right or wrong in any particular situation. But at least they're objective and easy to see to what extent your milage varies, vs. going to the local guru (group leader, VP, guy/gal with a drug on the market) and asking their off-the-cuff opion. As opinionated as Chris can be, that was a substantial service and he has my props.

For the record, I still believe in that great med chemists combine a combination of creativity, patern recognition based on implete data sets, intelligence, intensity, opportunism, obsessiveness and ego that isn't fully captured, and may never be, in any rule book I've seen. But there aren't in my experience very many great medicinal chemists out there.

xchemist: So the Rules simply aid the non-great to justify their need to stay in the comfort zone? Surely you have seen people justify their decisions to ignore/muddle/refuse/etc based on the Rules because it sounds better than no justification at all. If the Rules were a proven path to success, then we would all have a bit more job security.

RET: Agree on the antifungals thing... I'm not saying natural products suck... just that other methods are better at finding and validating new targets. There -ARE- heaps of top selling drugs which are derived from natural products, but outside of antiinfectives, most aren't from novel structural classes.

re: creativity -- We're formally evaluated against project performance. There's no tangible "creativity" box to score as I understand it, but "extracurriculars" / publications are definitely a way to improve your evaluation. I think it's more of a culture thing... If I have an idea on a new tool I'd like to develop (a reaction, equipment protocol, etc.) and if it won't slow down progress too much, it's encouraged.

It's always a balance... usually the best thing to do is plow through something the "old way" while you work on new approaches on the side.

Numbers do come up a lot for associate-level chemists, because their job is to crank out compounds... in my department, it definitely gets noticed if all of the compounds are pointless, though. Again... it's a balance.

>>>Why so negative? Several reasons. For one thing, this molecule is extremely greasy. This is not a killer in and of itself, but it’s inviting trouble, for the reasons noted here. The second problem is that this thing looks like it’s going to have some trouble dissolving. That’s trouble both from both the thermodynamic (eventual amount in solution) and kinetic (speed of dissolution) senses. .....

There is a company out there making amazing claims (www.wapisolutions.com) such as that they can prepare any API dispersed in water. I wonder if they could prepare this "greasy" molecule in water as well. Has anyone used their services? If they can do it, I would love to know if anyone has checked them out and validated their claims, since to me it sounds unbelievable.
Waterfreak